One of the defining features of addictive behavior is its persistence despite potentially severe adverse outcomes. To further understand why addicts fail to learn from negative outcomes, we propose to explore the role of a newly identified brain region, the rostromedial tegmental nucleus (RMTg), which we and others have recently shown to encode negative reward prediction errors, and to be critically involved in a variety of aversive behaviors. We hypothesize that impairment of this structure leads to an addiction phenotype in which animals persistently seek outcomes despite aversive outcomes. We propose two aims, the first of which is designed to better understand the basic mechanisms by which the RMTg contributes to learning about negative outcomes. Our second aim is more translational, exploring the role of the RMTg in cocaine-seeking under punishment, as well as its contribution to individual variation in propensity to develop addictive behaviors. PUBLIC HEALTH RELEVANCE: One hallmark of an addictive behavior is its persistence despite large negative outcomes, which can take a variety of forms, include physically aversive outcomes (withdrawal, toxicity) or social, cognitive, and financial losses. To better understand the pathology underlying these behaviors, we will explore the mechanisms underlying our recent findings that lesions of the rostromedial tegmental nucleus (RMTg) render animals strikingly deficient in learning from aversive outcomes. This will facilitate better treatments for behavioral disorders in which individuals seek drug rewards despite the large costs they incur.